Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)
| Autor: | Kailainathan, Sumangali, Piers, Thomas M., Yi, Jee Hyun, Choi, Seongmin, Fahey, Mark S., Borger, Eva, Gunn-Moore, Frank J., O’Neill, Laurie, Lever, Michael, Whitcomb, Daniel J., Cho, Kwangwook, Allen, Shelley J. |
|---|---|
| Přispěvatelé: | University of St Andrews. School of Biology, University of St Andrews. Institute of Behavioural and Neural Sciences, University of St Andrews. Biomedical Sciences Research Complex |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
DIV days in vitro IPTG isopropyl β-D-1-thiogalactopyranoside Long-Term Potentiation LD luminal domain chemical compounds studied in this article Hippocampus Mice LTP long-term potentiation NAD nicotinamide adenine dinucleotide binding kinetics CD circular dichroism ANOVA analysis of variance Cells Cultured Membrane Potential Mitochondrial Neurons Pro-brain-derived neurotrophic factor (proBDNF) Neuronal Plasticity LDH lactate dehydrogenase neurotrophin receptor TrkB tyrosine kinase B fEPSP field excitatory postsynaptic potentials Neurotrophin receptors SNP single nucleotide polymorphism Recombinant Proteins aCSF artificial cerebrospinal fluid PMS phenazinemethosulfate Chemical compounds studied in this article BDNF brain-derived neurotrophic factor Val66Met polymorphism JC-1 dye 5′ 6 6′-tetrachloro-1 1′ 3 3′-tetraethylbenzimidazolylcarbocyanine iodide neurotrophin receptors RM LTD long-term depression NDAS SPR surface plasmon resonance tau Proteins QH426 Genetics AD Alzheimer’s disease Article SDG 3 - Good Health and Well-being GSK3β glycogen synthase kinase 3β Animals Humans p75NTR pan-neurotrophin receptor FCR furin cleavage-resistant Protein Precursors Rats Wistar QH426 ComputingMethodologies_COMPUTERGRAPHICS Pharmacology PONDR predictor of naturally disordered regions Glycogen Synthase Kinase 3 beta Polymorphism Genetic L-Lactate Dehydrogenase Brain-Derived Neurotrophic Factor Long-term depression (LTD) ECD extracellular domain TrkBIg2 TrkB immunoglobulin-like domain 2 WT wild-type SDS PAGE sodium dodecyl sulfate polyacrylamide electrophoresis RM Therapeutics. Pharmacology long-term depression (LTD) Binding kinetics DTT dithiothreitol s.e.m. standard error of mean Synapses RU response units |
| Zdroj: | Kailainathan, S, Piers, T M, Yi, J H, Choi, S, Fahey, M S, Borger, E, Gunn-Moore, F J, O'Neill, L, Lever, M, Whitcomb, D J, Cho, K & Allen, S J 2016, ' Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF) ', Pharmacological Research, vol. 104, pp. 97-107 . https://doi.org/10.1016/j.phrs.2015.12.008 Kailainathan, S, Piers, T M, Yi, J H, Choi, S M, Fahey, M S, Borger, E, Gunn-Moore, F J, O'Neill, L, Lever, M, Whitcomb, D J, Cho, K & Allen, S J 2016, ' Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF) ', Pharmacological Research, vol. 104, pp. 97-107 . https://doi.org/10.1016/j.phrs.2015.12.008 Kailainathan, S, Piers, T M, Yi, J H, Choi, S, Fahey, M S, Borger, E, Gunn-Moore, F J, O'Neill, L, Lever, M, Whitcomb, D J, Cho, K & Allen, S J 2016, ' Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF) ', Pharmacological Research, vol. 104, no. 0, pp. 97-107 . https://doi.org/10.1016/j.phrs.2015.12.008 Pharmacological Research |
| DOI: | 10.1016/j.phrs.2015.12.008 |
| Popis: | Graphical abstract This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|